- Email: [email protected]
Fosfomycin for Pseudomonas-related exacerbations of cystic fibrosis
Letters to the Editor / International Journal of Antimicrobial Agents 32 (2008) 459–464
461
Table 1 Minimum inhibitory concentrations (MICs) of antimicrobial agents for VIM-1 metallo--lactamase-producing Citrobacter freundii C184/07, its transconjugant strain and Escherichia coli 26R793 Antibiotic
Imipenem Meropenem Ertapenem Aztreonam Ampicillin Amoxicillin/clavulanic acida Piperacillin/tazobactamb Ceftazidime Cefotaxime Cefuroxime Ciprofloxacin Netilmicin a b
Etest MIC (g/mL) C. freundii C184/07
Transconjugant strain
E. coli 26R793
4 0.5 1 1 >256 >256 >256 >256 >256 >256 1 12
2 0.25 0.125 0.5 >256 >256 >256 >256 64 >256 0.5 16
0.25 0.016 0.094 0.125 4 4 0.75 0.25 0.094 2 0.047 1.5
Amoxicillin/clavulanic acid 2:1. Tazobactam at a fixed concentration of 4 g/mL.
carditis and intra-abdominal sepsis have also been reported [6]. Citrobacter freundii isolates are usually susceptible to carbapenems and, at present, only a limited number of carbapenem-resistant strains have been identified. The mechanism of carbapenem resistance was mostly due to the acquisition of MBLs and occasionally hyperproduction of class C chromosomal cephalosporinase combined with reduced porin-mediated permeability [7]. These findings are of great concern because C. freundii, although considered a low virulence organism, is an important reservoir of resistance genes. The prompt and accurate detection of MBL-producing C. freundii strains is necessary to prevent the dissemination of resistance determinants to more virulent pathogens. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.
References [1] Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 2007;20:440–58. [2] Aschbacher R, Doumith M, Livermore DM, Larcher C, Woodford N. Linkage of acquired quinolone resistance (qnrS1) and metallo--lactamase (blaVIM−1 ) genes in multiple species of Enterobacteriaceae from Bolzano Italy. J Antimicrob Chemother 2008;61:515–23. [3] Weile J, Rahmig H, Gfröer S, Schroeppel K, Knabbe C, Susa M. First detection of a VIM-1 metallo-beta-lactamase in a carbapenem-resistant Citrobacter freundii clinical isolate in an acute hospital in Germany. Scand J Infect Dis 2007;39:264–6. [4] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Seventeenth informational supplement. M100-S17. Wayne, PA: CLSI; 2007. [5] Yan JJ, Hsueh PR, Ko WC, Luh KT, Tsai SH, Wu HM, et al. Metallo-beta-lactamases in clinical Pseudomonas isolates in Taiwan and identification of VIM-3, a novel variant of the VIM-2 enzyme. Antimicrob Agents Chemother 2001;45:2224–8. [6] Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–94. [7] Mainardi JL, Mugnier P, Coutrot A, Buu-Hoï A, Collatz E, Gutmann L. Carbapenem resistance in a clinical isolate of Citrobacter freundii. Antimicrob Agents Chemother 1997;41:2352–4.
Efthimia Protonotariou ∗ Maria Tsalidou Danai Vitti Department of Clinical Microbiology, Hippokration General Hospital, Konstantinoupoleos 49, Thessaloniki, Greece Athanasios Kalogeridis Department of Hematology, Laboratory of Molecular Biology, Second Department of Internal Medicine, Hippokration General Hospital, Thessaloniki, Greece
Danae Sofianou Department of Clinical Microbiology, Hippokration General Hospital, Konstantinoupoleos 49, Thessaloniki, Greece ∗ Corresponding
author. Tel.: +30 231 089 2050; fax: +30 231 089 2050. E-mail addresses: efi[email protected], [email protected] (E. Protonotariou)
doi:10.1016/j.ijantimicag.2008.05.008
Fosfomycin for Pseudomonas-related exacerbations of cystic fibrosis Sir, Patients with cystic fibrosis (CF) are particularly prone to infection with Pseudomonas aeruginosa and this plays a crucial role in pulmonary disease progression. Infective pulmonary exacerbations frequently require treatment with potent intravenous antipseudomonal antibiotics with their attending adverse-effect profile. Isolates are increasingly multidrug resistant and treatment is difficult [1]. Fosfomycin ((−)-cis-1,1-epoxy propyl phosphonic acid), originally termed phosphonomycin, is a broad-spectrum antibiotic first isolated in 1969 from Streptomyces spp. [2]. It acts by interfering with an early step of peptidoglycan synthesis and hence inhibits cell wall formation. Fosfomycin is bactericidal and has a broad spectrum of action that includes Pseudomonas spp., including multidrug-resistant Pseudomonas (MDRP) [3,4]. Fosfomycin has been shown to be active against P. aeruginosa growing in biofilms, which would theoretically be of particular benefit in the treatment of patients with CF [5]. Because it acts on a step in cell wall synthesis that is not affected by other classes of antibiotics, cross-resistance is unusual. Fosfomycin has a very good safety profile, with serious side effects being very uncommon. It is also thought to decrease the toxicity of other antibiotics by inhibiting the uptake of concomitantly administered drugs by renal tubular epithelial cells as well as by its effect on the stabilisation of lysosomal membranes [6]. Fosfomycin is also known to have anti-inflammatory and immunomodulatory properties, which again would be of particular benefit in CF patients [7]. In view of the above advantages, fosfomycin should be useful in the treatment of infective exacerbations in patients with CF, especially those due to MDRP; however, fosfomycin is not widely prescribed or recommended in guidelines. We report our experience using fosfomycin in the treatment of Pseudomonas-related infective exacerbations of CF over a period of 3 years.
462
Letters to the Editor / International Journal of Antimicrobial Agents 32 (2008) 459–464
Table 1 Pathogens cultured, sensitivity pattern and treatment Patient no.
Course no.
Pathogen 1
Sensitive toa
Pathogen 2
Sensitive toa
Fosfomycin combined with
1 2 3 3 3 4 4 4 4 4 4 4 4 4 4 4 5 5 5 6 7 7 7 7 7 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (M) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM)
Ta Co/To Co/Ci/Im Ta/Co/Ge Co/Ci/Ce Ta/To/Co Ta/To/Co Ta/To/Co Ta/To/Co Ta/Co Ta/Co/Ci Ta/Co Ta/To/Co Ta/To/Co Ta/To/Co To/Ge/Im Ta/Co Ta/Co Ta/Co Ta/To/Ce Ta Co Ta/Co Ta/Co Ce/Im/Ci Ta/To/Co
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M) MRSA
Ta/Ge/Ci Ta/To/Co Ta/To/Im Va/Li
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M)
To/Ce/Ci Ce/Ci/Im
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M)
Ce/Ci/Im Ce/Ci/Im Ta/To/Co
Ta/To Co To To To Ta/To Ta/To Ta/To Ta/To To Ta – Ta/To Ta/To Ta/To To To Co Co To To To To Ci To To
M, mucoid strain; NM, non-mucoid strain; MRSA, meticillin-resistant Staphylococcus aureus; Ce, ceftazidime; Ci, ciprofloxacin; Co, colistin; Ge, gentamicin; Im, imipenem; Li, linezolid; Ta, piperacillin/tazobactam; To, tobramycin; Va, vancomycin. a The Pseudomonas strain was resistant to all other antibiotics not documented as being sensitive to.
A diagnosis of an infective exacerbation was made if there was deterioration in the baseline respiratory symptoms with worsening cough, breathlessness and/or increased purulence of sputum. Patients were included in the study if they had previously grown Pseudomonas in the sputum and not responded to standard antibacterial treatment, had MDRP isolated or were intolerant to standard antibiotics. A previous adverse reaction to fosfomycin was the only exclusion criterion. Fosfomycin was given at a dose of 5 g intravenously every 8 h. The following were prospectively recorded: patient demographics; the number and duration of courses of fosfomycin prescribed; renal and liver function tests pre, during and post treatment; adverse effects; spirometry studies pre and post treatment; sputum culture; and sensitivities. The primary endpoint was symptomatic improvement. Data were analysed descriptively and statistical analysis was done using t-tests as appropriate. SPSS version 13.0 was used for statistical analysis, with a P-value of <0.05 considered significant. Fosfomycin was used to treat 26 pulmonary exacerbations in seven patients. The patient group comprised five females and two males with a mean age of 26.7 years (range 19–50 years). Fosfomycin was used as part of a combination of two or three antibiotics, except for one course where it was used as monotherapy. Eighteen courses were in combination with one other antibiotic and seven in combination with two. The organisms cultured, their sensitivity profile and the antibiotic regimen used are given in Table 1. Sixteen cultures grew non-mucoid strains of Pseudomonas alone. Nine cultures identified both mucoid and non-mucoid strains. One sample grew a mucoid isolate alone. The antibiotic sensitivity profile was available to antipseudomonal antibiotics, which included ceftazidime, imipenem, aztreonam, ciprofloxacin, piperacillin/tazobactam, gentamicin, amikacin, tobramycin and colistin. We do not perform routine fosfomycin sensitivity testing and hence these data are not available. In 22 of the 26 episodes treated, a Pseudomonas isolate was resistant to three or more of the above antibiotics.
The mean duration of antibiotic therapy was 14.3 days. In all the episodes treated there was symptomatic improvement. Mean urea, creatinine and alanine aminotransferase levels were similar before, during and at the end of treatment, with no significant changes noted. There were no adverse effects reported in any of the treated episodes. Mean forced expiratory volume in 1 s (FEV1 ) improved following treatment to 34.4% of predicted from 30.9% (P = 0.14). Analysing the group given fosfomycin in combination with an antibiotic to which the organism was resistant, the mean duration of treatment was similar (14 days) and so was the improvement in FEV1 (20–27% of predicted). A previous study from the UK has demonstrated good outcomes with fosfomycin in treating pulmonary exacerbations in CF, with improvement in pulmonary function as well as a good side effect profile [6]. Our study is an observational, open-label, clinical trial with no control group available for comparison. Our data lend support to the use of fosfomycin as part of a combination chemotherapy regimen in the treatment of Pseudomonas-related infective pulmonary exacerbations of CF. The use of fosfomycin should be considered especially when treating MDRP as well as when the use of standard antipseudomonal antibiotics is precluded due to drug-related reactions. Funding: No funding sources. Competing interests: None declared. Ethical approval: Fosfomycin was used following approval from the Drugs and Therapeutics committee of Castle Hill Hospital, Cottingham, UK. References [1] Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003;168: 918–51. [2] Hendlin D, Stapley EO, Jackson M, Wallick H, Miller AK, Wolf FJ, et al. Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 1969;166:122–3.
Letters to the Editor / International Journal of Antimicrobial Agents 32 (2008) 459–464 [3] Schülin T. In vitro activity of the aerosolized agents colistin and tobramycin and five intravenous agents against Pseudomonas aeruginosa isolated from cystic fibrosis patients in southwestern Germany. J Antimicrob Chemother 2002;49:403–6. [4] Tessier F, Quentin C. In vitro activity of fosfomycin combined with ceftazidime, imipenem, amikacin, and ciprofloxacin against Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 1997;16:159–62. [5] Rodríguez-Martínez JM, Ballesta S, Pascual A. Activity and penetration of fosfomycin, ciprofloxacin, amoxicillin/clavulanic acid and co-trimoxazole in Escherichia coli and Pseudomonas aeruginosa biofilms. Int J Antimicrob Agents 2007;30:366–8. [6] Mirakhur A, Gallagher MJ, Ledson MJ, Hart CA, Walshaw MJ. Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis. J Cyst Fibros 2003;2:19–24. [7] Zeitlinger M, Marsik C, Steiner I, Sauermann R, Seir K, Jilma B, et al. Immunomodulatory effects of fosfomycin in an endotoxin model in human blood. J Antimicrob Chemother 2007;59:219–23.
S. Faruqi ∗ J. McCreanor T. Moon Department of Academic Respiratory Medicine, Castle Hill Hospital, Cottingham HU16 5JQ, UK R. Meigh Department of Microbiology, Castle Hill Hospital, Cottingham HU16 5JQ, UK A.H. Morice Department of Academic Respiratory Medicine, Castle Hill Hospital, Cottingham HU16 5JQ, UK ∗ Corresponding
author. Tel.: +44 1482 624 967; fax: +44 1482 624 068. E-mail addresses: [email protected], [email protected] (S. Faruqi)
doi:10.1016/j.ijantimicag.2008.05.010
Prevalence of high-level vancomycin-resistant enterococci in French broilers and pigs Sir, National monitoring programmes were implemented in French slaughterhouses to evaluate the antimicrobial resistance of zoonotic (Campylobacter) and indicator (Escherichia coli and Enterococcus faecium) bacteria in 1999 in healthy broilers and in 2000 in pigs [1]. Avoparcin is an analogue of the glycopeptides vancomycin and teicoplanin used for human enterococci and staphylococci infections. Avoparcin was used in Europe for years as a growth promoter in animal husbandry but was banned in 1997 because of cross-resistance with vancomycin and teicoplanin, which are listed as ‘Critically Important Antimicrobials’ by the World Health Organization. Data from the French national monitoring programme indicated that no vancomycin-resistant E. faecium could be detected from broilers since 2002, and in pigs no vancomycin-resistant E. faecium was isolated in 2004. However, in human medicine, an increase in the proportion of vancomycin-resistant E. faecium was observed in 2004 and several epidemics due to VanA-type E. faecium were detected in 2005 [2]. To investigate the food origin of this phenomenon, it was decided to estimate the prevalence of high-level vancomycin-resistant enterococci, i.e. containing vanA or vanB genes, in broilers and pigs. Thus, caeca samples from broilers and faecal samples from pigs collected during the national monitoring programme in 2005 were obtained. Ten-fold dilutions were prepared and inoculated directly or after enrichment in bile salt broth (AES
463
Laboratories, Combourg, France) on bile aesculin azide agar (BioRad, Marnes-la-Coquette, France) medium supplemented with 6 mg/L vancomycin (Sigma, St. Quentin Fallavier, France). Cultures on medium without vancomycin were also performed to compare titres of total and resistant Enterococcus populations. Colonies detected on vancomycin plates and their vancomycin resistance genes were identified by polymerase chain reaction (PCR) according to Depardieu et al. [3]. The sensitivity of isolates was analysed by the microbroth dilution method [4]. In total, 193 chicken samples were obtained; 112 resulted in colonies on vancomycin media. However, after PCR analysis only three isolates (1.6%) were shown to contain the vanA gene, two of which were E. faecium (one isolated from an export broiler and the other from free-range production). The latter strain was isolated without enrichment. Of 113 tested pig samples, 71 resulted in colonies on vancomycin media. Seven samples (6.2%) contained vanA-positive Enterococcus spp. Four were E. faecium and one was Enterococcus faecalis. Three were not specified as E. faecalis, E. faecium, Enterococcus gallinarum or Enterococcus casseliflavus by PCR but were identified by biochemical tests as Enterococcus sp. Positive samples were detected from five different slaughterhouses from different geographical origins. For the five samples in which vancomycinresistant colonies could be detected without enrichment, the proportion of resistant enterococci/total enterococci was 1/500 to <1/15 000. The sensitivity of the isolates is shown in Table 1. All strains were resistant to vancomycin (minimum inhibitory concentration (MIC) = 32 mg/L for the E. faecalis isolate and MIC > 128 mg/L for the others) and to tetracycline. Most isolates were resistant to erythromycin, but none of them were resistant to ampicillin or gentamicin. It is also noteworthy that none of the isolates were resistant to avilamycin, in contrast to most of the vancomycinresistant strains isolated in 1999 [4]. Avilamycin is a food additive that was officially banned in 2006, but animal producers may have opted for a voluntary ban before this date. In conclusion, this study enabled detection of several vanAcontaining isolates in broiler and pig digestive flora 7 years after the avoparcin ban. No vanB-containing enterococci were detected. The prevalence was higher in pig production (P < 0.05). The antimicrobial resistance profiles of the isolates were rather different from those observed in recently isolated strains from human cases, as the human strains were usually resistant to ampicillin and frequently high-level resistant to gentamicin [2]. Finally, these observations regarding the prevalence of animals harbouring vancomycin-resistant strains are supported by the fact that during annual monitoring of the sensitivity of E. faecium strains isolated on non-selective media, no vancomycin-resistant strain was isolated from broilers in 2005 or 2006, but one and four resistant strains were detected in swine in 2005 and 2006, respectively (A. Perrin-Guyomard personal observation), figures that are still significantly much lower than the percentages observed just after the ban [1] and suggesting a marked decrease in the animal vancomycin resistance gene reservoir after the ban. In contrast, the prevalence of vanA-positive enterococci in humans did not change much as shown by the European Antimicrobial Resistance Surveillance System (EARSS) surveillance network data [5], which suggests that the avoparcin ban has had little influence on vancomycin resistance in enterococci of human origin. Actually, it appears that most hospital vancomycin-resistant enterococci belong to a subpopulation of hospital-adapted, epidemic strain types identified by multilocus sequence typing (MLST) – the so-called clonal complex CC-17 – distinct from animal strain types [6]. Although we did not determine the MLST type of our animal isolates, hypo-
461
Table 1 Minimum inhibitory concentrations (MICs) of antimicrobial agents for VIM-1 metallo--lactamase-producing Citrobacter freundii C184/07, its transconjugant strain and Escherichia coli 26R793 Antibiotic
Imipenem Meropenem Ertapenem Aztreonam Ampicillin Amoxicillin/clavulanic acida Piperacillin/tazobactamb Ceftazidime Cefotaxime Cefuroxime Ciprofloxacin Netilmicin a b
Etest MIC (g/mL) C. freundii C184/07
Transconjugant strain
E. coli 26R793
4 0.5 1 1 >256 >256 >256 >256 >256 >256 1 12
2 0.25 0.125 0.5 >256 >256 >256 >256 64 >256 0.5 16
0.25 0.016 0.094 0.125 4 4 0.75 0.25 0.094 2 0.047 1.5
Amoxicillin/clavulanic acid 2:1. Tazobactam at a fixed concentration of 4 g/mL.
carditis and intra-abdominal sepsis have also been reported [6]. Citrobacter freundii isolates are usually susceptible to carbapenems and, at present, only a limited number of carbapenem-resistant strains have been identified. The mechanism of carbapenem resistance was mostly due to the acquisition of MBLs and occasionally hyperproduction of class C chromosomal cephalosporinase combined with reduced porin-mediated permeability [7]. These findings are of great concern because C. freundii, although considered a low virulence organism, is an important reservoir of resistance genes. The prompt and accurate detection of MBL-producing C. freundii strains is necessary to prevent the dissemination of resistance determinants to more virulent pathogens. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.
References [1] Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 2007;20:440–58. [2] Aschbacher R, Doumith M, Livermore DM, Larcher C, Woodford N. Linkage of acquired quinolone resistance (qnrS1) and metallo--lactamase (blaVIM−1 ) genes in multiple species of Enterobacteriaceae from Bolzano Italy. J Antimicrob Chemother 2008;61:515–23. [3] Weile J, Rahmig H, Gfröer S, Schroeppel K, Knabbe C, Susa M. First detection of a VIM-1 metallo-beta-lactamase in a carbapenem-resistant Citrobacter freundii clinical isolate in an acute hospital in Germany. Scand J Infect Dis 2007;39:264–6. [4] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Seventeenth informational supplement. M100-S17. Wayne, PA: CLSI; 2007. [5] Yan JJ, Hsueh PR, Ko WC, Luh KT, Tsai SH, Wu HM, et al. Metallo-beta-lactamases in clinical Pseudomonas isolates in Taiwan and identification of VIM-3, a novel variant of the VIM-2 enzyme. Antimicrob Agents Chemother 2001;45:2224–8. [6] Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis 1999;28:384–94. [7] Mainardi JL, Mugnier P, Coutrot A, Buu-Hoï A, Collatz E, Gutmann L. Carbapenem resistance in a clinical isolate of Citrobacter freundii. Antimicrob Agents Chemother 1997;41:2352–4.
Efthimia Protonotariou ∗ Maria Tsalidou Danai Vitti Department of Clinical Microbiology, Hippokration General Hospital, Konstantinoupoleos 49, Thessaloniki, Greece Athanasios Kalogeridis Department of Hematology, Laboratory of Molecular Biology, Second Department of Internal Medicine, Hippokration General Hospital, Thessaloniki, Greece
Danae Sofianou Department of Clinical Microbiology, Hippokration General Hospital, Konstantinoupoleos 49, Thessaloniki, Greece ∗ Corresponding
author. Tel.: +30 231 089 2050; fax: +30 231 089 2050. E-mail addresses: efi[email protected], [email protected] (E. Protonotariou)
doi:10.1016/j.ijantimicag.2008.05.008
Fosfomycin for Pseudomonas-related exacerbations of cystic fibrosis Sir, Patients with cystic fibrosis (CF) are particularly prone to infection with Pseudomonas aeruginosa and this plays a crucial role in pulmonary disease progression. Infective pulmonary exacerbations frequently require treatment with potent intravenous antipseudomonal antibiotics with their attending adverse-effect profile. Isolates are increasingly multidrug resistant and treatment is difficult [1]. Fosfomycin ((−)-cis-1,1-epoxy propyl phosphonic acid), originally termed phosphonomycin, is a broad-spectrum antibiotic first isolated in 1969 from Streptomyces spp. [2]. It acts by interfering with an early step of peptidoglycan synthesis and hence inhibits cell wall formation. Fosfomycin is bactericidal and has a broad spectrum of action that includes Pseudomonas spp., including multidrug-resistant Pseudomonas (MDRP) [3,4]. Fosfomycin has been shown to be active against P. aeruginosa growing in biofilms, which would theoretically be of particular benefit in the treatment of patients with CF [5]. Because it acts on a step in cell wall synthesis that is not affected by other classes of antibiotics, cross-resistance is unusual. Fosfomycin has a very good safety profile, with serious side effects being very uncommon. It is also thought to decrease the toxicity of other antibiotics by inhibiting the uptake of concomitantly administered drugs by renal tubular epithelial cells as well as by its effect on the stabilisation of lysosomal membranes [6]. Fosfomycin is also known to have anti-inflammatory and immunomodulatory properties, which again would be of particular benefit in CF patients [7]. In view of the above advantages, fosfomycin should be useful in the treatment of infective exacerbations in patients with CF, especially those due to MDRP; however, fosfomycin is not widely prescribed or recommended in guidelines. We report our experience using fosfomycin in the treatment of Pseudomonas-related infective exacerbations of CF over a period of 3 years.
462
Letters to the Editor / International Journal of Antimicrobial Agents 32 (2008) 459–464
Table 1 Pathogens cultured, sensitivity pattern and treatment Patient no.
Course no.
Pathogen 1
Sensitive toa
Pathogen 2
Sensitive toa
Fosfomycin combined with
1 2 3 3 3 4 4 4 4 4 4 4 4 4 4 4 5 5 5 6 7 7 7 7 7 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (M) P. aeruginosa (NM) P. aeruginosa (NM) P. aeruginosa (NM)
Ta Co/To Co/Ci/Im Ta/Co/Ge Co/Ci/Ce Ta/To/Co Ta/To/Co Ta/To/Co Ta/To/Co Ta/Co Ta/Co/Ci Ta/Co Ta/To/Co Ta/To/Co Ta/To/Co To/Ge/Im Ta/Co Ta/Co Ta/Co Ta/To/Ce Ta Co Ta/Co Ta/Co Ce/Im/Ci Ta/To/Co
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M) MRSA
Ta/Ge/Ci Ta/To/Co Ta/To/Im Va/Li
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M)
To/Ce/Ci Ce/Ci/Im
P. aeruginosa (M) P. aeruginosa (M) P. aeruginosa (M)
Ce/Ci/Im Ce/Ci/Im Ta/To/Co
Ta/To Co To To To Ta/To Ta/To Ta/To Ta/To To Ta – Ta/To Ta/To Ta/To To To Co Co To To To To Ci To To
M, mucoid strain; NM, non-mucoid strain; MRSA, meticillin-resistant Staphylococcus aureus; Ce, ceftazidime; Ci, ciprofloxacin; Co, colistin; Ge, gentamicin; Im, imipenem; Li, linezolid; Ta, piperacillin/tazobactam; To, tobramycin; Va, vancomycin. a The Pseudomonas strain was resistant to all other antibiotics not documented as being sensitive to.
A diagnosis of an infective exacerbation was made if there was deterioration in the baseline respiratory symptoms with worsening cough, breathlessness and/or increased purulence of sputum. Patients were included in the study if they had previously grown Pseudomonas in the sputum and not responded to standard antibacterial treatment, had MDRP isolated or were intolerant to standard antibiotics. A previous adverse reaction to fosfomycin was the only exclusion criterion. Fosfomycin was given at a dose of 5 g intravenously every 8 h. The following were prospectively recorded: patient demographics; the number and duration of courses of fosfomycin prescribed; renal and liver function tests pre, during and post treatment; adverse effects; spirometry studies pre and post treatment; sputum culture; and sensitivities. The primary endpoint was symptomatic improvement. Data were analysed descriptively and statistical analysis was done using t-tests as appropriate. SPSS version 13.0 was used for statistical analysis, with a P-value of <0.05 considered significant. Fosfomycin was used to treat 26 pulmonary exacerbations in seven patients. The patient group comprised five females and two males with a mean age of 26.7 years (range 19–50 years). Fosfomycin was used as part of a combination of two or three antibiotics, except for one course where it was used as monotherapy. Eighteen courses were in combination with one other antibiotic and seven in combination with two. The organisms cultured, their sensitivity profile and the antibiotic regimen used are given in Table 1. Sixteen cultures grew non-mucoid strains of Pseudomonas alone. Nine cultures identified both mucoid and non-mucoid strains. One sample grew a mucoid isolate alone. The antibiotic sensitivity profile was available to antipseudomonal antibiotics, which included ceftazidime, imipenem, aztreonam, ciprofloxacin, piperacillin/tazobactam, gentamicin, amikacin, tobramycin and colistin. We do not perform routine fosfomycin sensitivity testing and hence these data are not available. In 22 of the 26 episodes treated, a Pseudomonas isolate was resistant to three or more of the above antibiotics.
The mean duration of antibiotic therapy was 14.3 days. In all the episodes treated there was symptomatic improvement. Mean urea, creatinine and alanine aminotransferase levels were similar before, during and at the end of treatment, with no significant changes noted. There were no adverse effects reported in any of the treated episodes. Mean forced expiratory volume in 1 s (FEV1 ) improved following treatment to 34.4% of predicted from 30.9% (P = 0.14). Analysing the group given fosfomycin in combination with an antibiotic to which the organism was resistant, the mean duration of treatment was similar (14 days) and so was the improvement in FEV1 (20–27% of predicted). A previous study from the UK has demonstrated good outcomes with fosfomycin in treating pulmonary exacerbations in CF, with improvement in pulmonary function as well as a good side effect profile [6]. Our study is an observational, open-label, clinical trial with no control group available for comparison. Our data lend support to the use of fosfomycin as part of a combination chemotherapy regimen in the treatment of Pseudomonas-related infective pulmonary exacerbations of CF. The use of fosfomycin should be considered especially when treating MDRP as well as when the use of standard antipseudomonal antibiotics is precluded due to drug-related reactions. Funding: No funding sources. Competing interests: None declared. Ethical approval: Fosfomycin was used following approval from the Drugs and Therapeutics committee of Castle Hill Hospital, Cottingham, UK. References [1] Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003;168: 918–51. [2] Hendlin D, Stapley EO, Jackson M, Wallick H, Miller AK, Wolf FJ, et al. Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 1969;166:122–3.
Letters to the Editor / International Journal of Antimicrobial Agents 32 (2008) 459–464 [3] Schülin T. In vitro activity of the aerosolized agents colistin and tobramycin and five intravenous agents against Pseudomonas aeruginosa isolated from cystic fibrosis patients in southwestern Germany. J Antimicrob Chemother 2002;49:403–6. [4] Tessier F, Quentin C. In vitro activity of fosfomycin combined with ceftazidime, imipenem, amikacin, and ciprofloxacin against Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 1997;16:159–62. [5] Rodríguez-Martínez JM, Ballesta S, Pascual A. Activity and penetration of fosfomycin, ciprofloxacin, amoxicillin/clavulanic acid and co-trimoxazole in Escherichia coli and Pseudomonas aeruginosa biofilms. Int J Antimicrob Agents 2007;30:366–8. [6] Mirakhur A, Gallagher MJ, Ledson MJ, Hart CA, Walshaw MJ. Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis. J Cyst Fibros 2003;2:19–24. [7] Zeitlinger M, Marsik C, Steiner I, Sauermann R, Seir K, Jilma B, et al. Immunomodulatory effects of fosfomycin in an endotoxin model in human blood. J Antimicrob Chemother 2007;59:219–23.
S. Faruqi ∗ J. McCreanor T. Moon Department of Academic Respiratory Medicine, Castle Hill Hospital, Cottingham HU16 5JQ, UK R. Meigh Department of Microbiology, Castle Hill Hospital, Cottingham HU16 5JQ, UK A.H. Morice Department of Academic Respiratory Medicine, Castle Hill Hospital, Cottingham HU16 5JQ, UK ∗ Corresponding
author. Tel.: +44 1482 624 967; fax: +44 1482 624 068. E-mail addresses: [email protected], [email protected] (S. Faruqi)
doi:10.1016/j.ijantimicag.2008.05.010
Prevalence of high-level vancomycin-resistant enterococci in French broilers and pigs Sir, National monitoring programmes were implemented in French slaughterhouses to evaluate the antimicrobial resistance of zoonotic (Campylobacter) and indicator (Escherichia coli and Enterococcus faecium) bacteria in 1999 in healthy broilers and in 2000 in pigs [1]. Avoparcin is an analogue of the glycopeptides vancomycin and teicoplanin used for human enterococci and staphylococci infections. Avoparcin was used in Europe for years as a growth promoter in animal husbandry but was banned in 1997 because of cross-resistance with vancomycin and teicoplanin, which are listed as ‘Critically Important Antimicrobials’ by the World Health Organization. Data from the French national monitoring programme indicated that no vancomycin-resistant E. faecium could be detected from broilers since 2002, and in pigs no vancomycin-resistant E. faecium was isolated in 2004. However, in human medicine, an increase in the proportion of vancomycin-resistant E. faecium was observed in 2004 and several epidemics due to VanA-type E. faecium were detected in 2005 [2]. To investigate the food origin of this phenomenon, it was decided to estimate the prevalence of high-level vancomycin-resistant enterococci, i.e. containing vanA or vanB genes, in broilers and pigs. Thus, caeca samples from broilers and faecal samples from pigs collected during the national monitoring programme in 2005 were obtained. Ten-fold dilutions were prepared and inoculated directly or after enrichment in bile salt broth (AES
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Laboratories, Combourg, France) on bile aesculin azide agar (BioRad, Marnes-la-Coquette, France) medium supplemented with 6 mg/L vancomycin (Sigma, St. Quentin Fallavier, France). Cultures on medium without vancomycin were also performed to compare titres of total and resistant Enterococcus populations. Colonies detected on vancomycin plates and their vancomycin resistance genes were identified by polymerase chain reaction (PCR) according to Depardieu et al. [3]. The sensitivity of isolates was analysed by the microbroth dilution method [4]. In total, 193 chicken samples were obtained; 112 resulted in colonies on vancomycin media. However, after PCR analysis only three isolates (1.6%) were shown to contain the vanA gene, two of which were E. faecium (one isolated from an export broiler and the other from free-range production). The latter strain was isolated without enrichment. Of 113 tested pig samples, 71 resulted in colonies on vancomycin media. Seven samples (6.2%) contained vanA-positive Enterococcus spp. Four were E. faecium and one was Enterococcus faecalis. Three were not specified as E. faecalis, E. faecium, Enterococcus gallinarum or Enterococcus casseliflavus by PCR but were identified by biochemical tests as Enterococcus sp. Positive samples were detected from five different slaughterhouses from different geographical origins. For the five samples in which vancomycinresistant colonies could be detected without enrichment, the proportion of resistant enterococci/total enterococci was 1/500 to <1/15 000. The sensitivity of the isolates is shown in Table 1. All strains were resistant to vancomycin (minimum inhibitory concentration (MIC) = 32 mg/L for the E. faecalis isolate and MIC > 128 mg/L for the others) and to tetracycline. Most isolates were resistant to erythromycin, but none of them were resistant to ampicillin or gentamicin. It is also noteworthy that none of the isolates were resistant to avilamycin, in contrast to most of the vancomycinresistant strains isolated in 1999 [4]. Avilamycin is a food additive that was officially banned in 2006, but animal producers may have opted for a voluntary ban before this date. In conclusion, this study enabled detection of several vanAcontaining isolates in broiler and pig digestive flora 7 years after the avoparcin ban. No vanB-containing enterococci were detected. The prevalence was higher in pig production (P < 0.05). The antimicrobial resistance profiles of the isolates were rather different from those observed in recently isolated strains from human cases, as the human strains were usually resistant to ampicillin and frequently high-level resistant to gentamicin [2]. Finally, these observations regarding the prevalence of animals harbouring vancomycin-resistant strains are supported by the fact that during annual monitoring of the sensitivity of E. faecium strains isolated on non-selective media, no vancomycin-resistant strain was isolated from broilers in 2005 or 2006, but one and four resistant strains were detected in swine in 2005 and 2006, respectively (A. Perrin-Guyomard personal observation), figures that are still significantly much lower than the percentages observed just after the ban [1] and suggesting a marked decrease in the animal vancomycin resistance gene reservoir after the ban. In contrast, the prevalence of vanA-positive enterococci in humans did not change much as shown by the European Antimicrobial Resistance Surveillance System (EARSS) surveillance network data [5], which suggests that the avoparcin ban has had little influence on vancomycin resistance in enterococci of human origin. Actually, it appears that most hospital vancomycin-resistant enterococci belong to a subpopulation of hospital-adapted, epidemic strain types identified by multilocus sequence typing (MLST) – the so-called clonal complex CC-17 – distinct from animal strain types [6]. Although we did not determine the MLST type of our animal isolates, hypo-